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Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature.

ABSTRACT: Height is a heritable and highly heterogeneous trait. Short stature affects 3% of the population and in most cases is genetic in origin. After excluding known causes, 67% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.

SUBMITTER: Hauer NN

PROVIDER: S-EPMC6777496 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature.

Hauer Nadine N NN Popp Bernt B Taher Leila L Vogl Carina C Dhandapany Perundurai S PS Büttner Christian C Uebe Steffen S Sticht Heinrich H Ferrazzi Fulvia F Ekici Arif B AB De Luca Alessandro A Klinger Patrizia P Kraus Cornelia C Zweier Christiane C Wiesener Antje A Jamra Rami Abou RA Kunstmann Erdmute E Rauch Anita A Wieczorek Dagmar D Jung Anna-Marie AM Rohrer Tilman R TR Zenker Martin M Doerr Helmuth-Guenther HG Reis André A Reis André A Thiel Christian T CT

European journal of human genetics : EJHG 20190226 7

Height is a heritable and highly heterogeneous trait. Short stature affects 3% of the population and in most cases is genetic in origin. After excluding known causes, 67% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36%) independent families. Based on systematic characterization of variants and f ...[more]

PMID: 30809043

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Project description:The use of appropriate growth standards/references is of significant clinical importance in assessing the height of children with short stature as it may determine eligibility for appropriate therapy. The aim of this study was to determine the impact of using World Health Organization (WHO) instead of national growth standards/references on height assessment in short children. Data were collected from routine clinical practice (1998-2014) from nine European countries that have available national growth references and were enrolled in NordiNet® International Outcome Study (IOS) (NCT00960128), a large-scale, non-interventional, multinational study. The patient cohort consisted of 5996 short pediatric patients diagnosed with growth hormone deficiency (GHD), Turner syndrome (TS) or born small for gestational age (SGA). The proportions of children with baseline height standard deviation score (SDS) below clinical cut-off values (-2 SDS for GHD and TS; -2.5 SDS for SGA) based on national growth references and WHO growth standards/references were compared for children aged <5 years and children aged ≥5 years. In seven of the countries evaluated, significantly fewer children aged ≥5 years with GHD (22%; P<0.0001), TS (21%; P<0.0001) or born SGA (32%; P<0.0001) had height below clinical cut-off values using WHO growth references vs. national references. Likewise, among children aged <5 years in the pooled analysis of the same seven countries, a significantly lower proportion of children with GHD (8%; P<0.0001), TS (12%; P = 0.0003) or born SGA (12%; P<0.0001) had height below clinical cut-off values using WHO growth standards vs. national references. In conclusion, in NordiNet® IOS the number of patients misclassified using WHO growth standards/references was significantly higher than with national references. This study highlights that, although no growth reference has 100% sensitivity for identifying growth disorders, the most recent national or regional growth charts may offer the most appropriate tool for monitoring childhood growth in Europe.

Project description:BackgroundChildren with Idiopathic Short Stature do not attain a normal adult height. The improvement of adult height with treatment with recombinant human growth hormone (rhGH), at doses of 0.16 to 0.28 mg/kg/week is modest, usually less that 4 cm, and they remain short as adults. The benefit obtained seems dose dependent and benefits of 7.0 to 8.0 cm have been reported with higher doses of 0.32 to 0.4 mg/kg/week, but the number of studies is limited. The topic has remained controversial.ObjectiveThe objective was to conduct a retrospective analysis of our experience with 123 children with ISS treated with 0.32 ± 0.03 mg/kg/week of rhGH, with the aim of comparing the different subgroups of non-familial short stature, familial short stature, normal puberty, and delayed puberty and to assess the benefit by comparison with 305 untreated historical controls, from nine different randomized and nonrandomized controlled studies.ResultsEighty eight of our children (68 males and 20 females) attained an adult height or near adult height of -0.71 SDS (0.74 SD) (95% CI, -0.87 to -0.55) with a benefit over untreated controls of 9.5 cm (7.4 to 11.6 cm) for males and 8.6 cm (6.7 to 10.5 cm) for females. In the analysis of the subgroups, the adult height and adult height gain of children with non-familial short stature were significantly higher than of familial short stature. No difference was found in the cohorts with normal or delayed puberty in any of the subgroups, except between the non-familial short stature and familial short stature puberty cohorts. This has implications for the interpretation of the benefit of treatment in studies where the number of children with familial short stature in the controls or treated subjects is not known. The treatment was safe. There were no significant adverse events. The IGF-1 values were essentially within the levels expected for the stages of puberty.ConclusionOur experience was quite positive with normalization of the heights and growth of the children during childhood and the attainment of normal adult heights, the main two aims of treatment.

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Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature.

Publications

Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature.

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